A large number of pharmacologically active substances have a potential for being intentionally or unintentionally abused or misused, i.e. they can be used to produce effects which are not consistent with their intended use. Thus, e.g. opioids which exhibit an excellent efficacy in controlling severe to extremely severe pain are frequently abused to induce euphoric states similar to being intoxicated. In particular, active substances which have a psychotropic effect are abused accordingly.
To intentionally enable abuse, the corresponding pharmaceutical dosage forms, such as pharmaceutical dosage forms or capsules can be taken with alcohol (oral abuse). Alternatively, the dosage forms are crushed, for example ground by the abuser, the active substance is extracted from the thus obtained powder using a preferably aqueous liquid and after being optionally filtered through cotton wool or cellulose wadding, the resultant solution is administered parenterally, in particular intravenously. This type of dosage results in an even faster diffusion of the active substance compared to the oral abuse, with the result desired by the abuser, namely the kick. This kick or these intoxication-like, euphoric states are also reached if the powdered pharmaceutical dosage form is administered nasally, i.e. is sniffed.
However, sometimes patients unintentionally disrupt the controlled release properties of dosage forms by concomitant consumption of alcoholic beverages, thereby inducing dose dumping. Dosage forms containing active ingredients having a high solubility in water usually have a high susceptibility to ethanolic dose dumping.
Various concepts for the avoidance of intentional and unintentional drug abuse have been developed.
It has been proposed to incorporate in pharmaceutical dosage forms aversive agents and/or antagonists in a manner so that they only produce their aversive and/or antagonizing effects when the pharmaceutical dosage forms are tampered with. However, the presence of such aversive agents is principally not desirable and there is a need to provide sufficient tamper-resistance without relying on aversive agents and/or antagonists.
Another concept to prevent abuse relies on the mechanical properties of the pharmaceutical dosage forms, particularly an increased breaking strength (resistance to crushing). The major advantage of such pharmaceutical dosage forms is that comminuting, particularly pulverization, by conventional means, such as grinding in a mortar or fracturing by means of a hammer, is impossible or at least substantially impeded. Thus, the pulverization, necessary for abuse, of the pharmaceutical dosage forms by the means usually available to a potential abuser is prevented or at least complicated. Such pharmaceutical dosage forms are useful for avoiding drug abuse of the pharmacologically active ingredient contained therein, as they may not be powdered by conventional means and thus, cannot be administered in powdered form, e.g. nasally. The mechanical properties, particularly the high breaking strength of these pharmaceutical dosage forms renders them tamper-resistant. In the context of such tamper-resistant pharmaceutical dosage forms it can be referred to, e.g., WO 2005/016313, WO 2005/016314, WO 2005/063214, WO 2005/102286, WO 2006/002883, WO 2006/002884, WO 2006/002886, WO 2006/082097, WO 2006/082099, and WO2009/092601.
However, besides tampering of pharmaceutical dosage forms in order to abuse the drugs contained therein, the potential impact of concomitant intake of ethanol on the in vivo release of drugs from modified release oral formulations (dose-dumping) has recently become an increasing concern. Controlled or modified release formulations typically contain a higher amount of the pharmacologically active ingredient relative to its immediate release counterpart. If the controlled release portion of the formulation is easily defeated, the end result is a potential increase in exposure to the active drug and possible safety concerns. In order to improve safety and circumvent intentional tampering (e.g. dissolving a controlled release pharmaceutical dosage form in ethanol to extract the drug), a reduction in the dissolution of the modified release fractions of such formulations, in ethanol, may be of benefit.
For monolithic dosage forms some formulation concepts are known which provide to some degree a controlled release of the drug substance even in ethanolic media. Further, however, monolithic dosage forms are not suitable for all patient groups, as they are required to be swallowed intact. Due to the big size of such formulations this is not possible for patients having difficulties in swallowing as e.g. the elderly and children. These patients have a high risk of choking on monolithic dosage forms. Pulverization of these dosage forms on the other hand solves the choking hazard, but endangers the patients by releasing a potentially toxic dose of the drug substance.
The swallowing issue can be overcome by the use of multiparticulate dosage forms, e.g. MUPS (multiple unit pellet system) tablets or capsules filled with controlled release granules, which can be reduced in size to the size of the individual particles without losing the control of the drug release. In contrast to the above mentioned monolithic formulations, obtaining functional robustness in ethanolic media of the multiparticulate formulations is a challenge. Working examples of monolithic dosage forms contain hydrophilic polymer matrices, wherein control of drug release is achieved by a long diffusion way within the formulation. For multiparticulate forms, long diffusion ways do not exist due to the small size of the individual particles. A common technique to overcome this problem is the application of a functional barrier coating on top of the individual particle, e.g. ethylcellulose for diffusion control. However, as ethylcellulose is alcohol soluble, these formulation approaches are not resistant against ethanolic dose dumping.
Accordingly, the need exists to develop new formulations having reduced potential for dose dumping in alcohol.
US 2008/0085304 discloses robust sustained release formulations, solid dosage forms comprising robust sustained release formulations, and methods for making and using these formulations and solid dosage forms are provided. Robustness of the sustained release formulation is related to the particle size of the hydrophilic gum. Sustained release formulations resist dose-dumping when ingested with alcohol. The formulations are useful for treating a patient suffering from a condition, e.g., pain. The formulations comprise at least one drug. In one embodiment, the drug is an opioid, e.g., oxymorphone.
WO 2009/034541 relates to a solid dosage form for the controlled release of trimetazidine suitable for once-daily dosing, in which the dosage form exhibits a controlled in vitro release of trimetazidine in phosphate buffer at pH 6.8 of not less than about 75% after 16 hours when measured using USP Apparatus I at 100 rpm, thereby decreasing the incidence and severity of burst release or dose dumping.
WO 2013/084059 relates to a pharmaceutical dosage form comprising a mixture in the form of an extended release matrix formulation, the mixture comprising at least: (1) at least one poly(ε-caprolactone), and (2) at least one polyethylene oxide, and (3) at least one active agent. The dosage form is said to be tamper resistant and to provide extended release of the active agent. However, poly(ε-caprolactone) is not a pharmacopeial excipient for oral use according to the Ph. Eur. and the USP, respectively.
WO 2012/166474 relates to a solid dose form comprising a film coating composition encapsulating a core, wherein the core comprises an active ingredient comprising at least one of a pharmaceutical, veterinary, or nutraceutical active ingredient; the film coating composition comprises ethylcellulose and guar gum; and the guar gum is present in an amount greater than 5 wt % based on the weight of the guar gum and ethylcellulose. The solid dose form is said to provide controlled release of the active ingredient and to be ethanol resistant. Extended release tablets comprising a lipid matrix containing glyceryl (di)behenate (commercially available as Compritol® 888 ATO) in which the active ingredient is embedded are said to not being susceptible to alcohol-related dose dumping. The drug substance is said to be released from the dosage form by diffusion, thereby leaving behind an in principle structurally intact tablet matrix. However, this is not satisfactory in every respect. The remaining “washed-out” lipid tablet will remain visible in human stool after excretion. This observation (“ghosting”) is known to lead to increased complaints by patients and a reduced patient compliance. Further, mechanical manipulation of the tablet e.g. dividing it to allow easier swallowing, leads to an accelerated drug release due to reduced diffusion ways eventually resulting in higher plasma concentrations of the drug substance including toxic levels.
However, the properties of these pharmaceutical dosage forms of the prior art, however, are not satisfactory in every respect.